We will test if leptin receptor signaling in intestinal epithelial cells (IECs) protects from intestinal infection due to Entamoeba histolytica, both intrinsically within IECs by up-regulating repair pathways, and extrinsically by IEC-mediated recruitment of inflammatory cells to the intestine. Successful completion of these studies will identify the mechanism by which leptin receptor signaling acts in mucosal defense, with implications for the understanding of gut immune homeostasis. Significance: The importance of this project derives from the contribution of malnutrition to an estimated one-third of all deaths among children and 60% of deaths due to diarrhea, and to the contribution of amebiasis to severe diarrhea in children in the developing world. Innovative aspects of the proposal include that it challenges the existing paradigm that protein-energy malnutrition explains the infectious diseases susceptibility of malnourished children. In contrast this study identifies specific leptin mediated molecular pathways in intestinal epithelial cells that are altered in malnourished children and that contribute to infectious disease susceptibility The environment for the work includes active investigation of amebiasis in humans, murine models, and at the cellular level, and the Principal Investigator who has contributed to amebiasis research for over 25 years. PUBLIC HEALTH RELEVANCE: Malnutrition contributes to an estimated one-third of all deaths among children and 60% of deaths due to diarrhea. This proposal will identify the mechanism by which lack of the nutritional hormone leptin increases susceptibility to amebiasis, with the potential of more broadly understanding why malnourished children suffer disproportionately from diarrhea.